Tissue adhesives have been increasingly used to enhance traditional closure technologies such as sutures and staples, offering improved sealing capabilities and plugging of undesired leaks1. However, despite recent developments and increased clinical demand, currently available products still suffer from serious drawbacks. While synthetic adhesives have low biocompatibility, low adherence to wet surfaces and potential toxicity, the biological glues are costly, often show relatively poor mechanical and tissue-bonding properties, and are potentially immunogenic, as most of them are based on proteins. Thus, there is a genuine unmet need for non-toxic, strong, and economical tissue sealants to sustain internal surgical incision closure, as an adjunct to suturing or stapling. This need was the main motivation for the development of bio-mimicking adhesives, which received increasing attention in the last decade.
Using an adhesive for tissue reattachments or repair procedures usually require the adhesive to be applied onto a hydrated tissue surface. Moreover, biomedical adhesives have to overcome contact with physiological fluids such as blood or saline in order to form contacts or associations with the underlying tissue. The success of synthetic adhesives in a hydrated environment is limited, and typically requires certain treatments and/or performing partial dehydration of the contact surface2. In contrast to synthetic materials, nature has very effectively conquered the limitations of sticking to wet surfaces3. Marine sessile organisms such as barnacles, reef worms, mussels, algae have life histories that depend on their secure attachment to solid substrate for survival. These organisms produce and secrete adhesives that form permanent, strong and flexible underwater bonds to virtually any hard surface4. For example, mussels attach to wet surfaces by creating a byssus, an extracorporeal bundle of tiny tendons that are attached distally to a foreign substratum and proximally by insertion of the stem root into the byssal retractor muscles. “Mussel glues” have been proposed to be suitable for medical applications due to their high adhesion strength and their ability to adhere to wet surfaces. However, it is clear that the commercial production of such glues is currently not practical, since extraction of 1 kg of the naturally existing adhesive raw materials (proteins and polypeptides) would require processing five to ten million mussels1.
An alternative and more practical method is based on taking a ‘biomimetic’ approach, which entails constructing artificial materials that mimic natural forms. Polymeric analogs may be synthesized, as an example, from amino acids that were identified as being functional to naturally existing adhesive proteins. Much effort has been made to synthesize random block copolymers, which are biomimetic approximations of naturally existing adhesive proteins and polypeptides2, 8-20.
Another effective natural adhesion mechanism exists in red and brown algae, which produce phenolic compounds that exhibit adhesive properties and extraordinarily high cohesive strength. These adhesive contain phenolic compounds that bind non-specifically to both hydrophobic and hydrophilic surfaces in aqueous conditions21. The secretion of these phenolic compounds is coupled with peroxidase oxidation and results in their crosslinking of cell-wall polysaccharides. Based on those observations, Vreeland et al. disclosed in U.S. Pat. No. 5,520,727 entitled “Aqueous algal-based phenolic type adhesives and glues” in which the algal-based phloroglucinol was activated and cross linked with algal carbohydrates in order to form glue. The inventors of the present invention have demonstrated that formulations composed of oxidized polyphenol extracted from Fucus serratus, alginate and calcium ions are capable of adhering to a variety of surfaces23. Structural analysis using small angle x-ray scattering (SAXS) and electron microscopy (cryo-TEM) showed that the polyphenols self-assemble into chain-like objects24. Oxidation did not alter this overall structure, causing only a reduction in the aggregate size. Moreover, this chain-like structure did not change upon addition of alginate. Once calcium ions were added, a network (whose overall structure resembled that of the alginate gel) was formed.
Since the production of nature-based glues such as disclosed in Vreeland et al. and others rely on extracting natural materials from tons of algae, there was a need to synthetically imitate the remarkable ability of marine algae to attach to wet solid surface in order to provide effective adhesives having characteristics that are similar to the characteristics of the marine algae.
Using the biomimetic approach, the inventors of the present invention hypothesized that the natural components of the “fucus glue” can be successfully replaced with commercially available analogue that provides similar functionally. In PCT/IL2006/000289, the inventors of the present invention indeed showed that the monomeric unit of phloroglucinol and several of its derivatives to interact with polysaccharide such as alginate to form an adhesive that was shown to adhere in various compositions to animal tissues as well as to other surfaces.
Interactions between carbohydrates and polyphenols are not unique to algae adhesives. Polyphenols are a large and very diverse family of plant metabolites, characterized by the presence of more than one phenol group per molecule25-30.
It is needed to extend the adhesive composition beyond the biomimetic approach and to develop adhesive composition of matter that are able to form strong interactions with surfaces, whether dry or wet, as well as within the network itself.
Moreover, the method of applying the adhesive materials seems to play an important role in the ability to utilize the adhesive composition of matter as an effective sealant. The inventors of the present invention developed methods of applying the adhesive material that allow on-site curing of the adhesive and usage of bandages that form with the adhesive material an affective sealant especially for medical use.